Population Pharmacokinetic Model of Methotrexate in Brazilian Pediatric Patients with Acute Lymphoblastic Leukemia.
Pharm Res
; 40(7): 1777-1787, 2023 Jul.
Article
em En
| MEDLINE
| ID: mdl-37291462
OBJECTIVES: Methotrexate (MTX) is subject to therapeutic drug monitoring because of its high pharmacokinetic variability and safety risk outside the therapeutic window. This study aimed to develop a population pharmacokinetic model (popPK) of MTX for Brazilian pediatric acute lymphoblastic leukemia (ALL) patients who attended the Hospital de Clínicas de Porto Alegre, Brazil. METHODS: The model was developed using NONMEM 7.4 (Icon®), ADVAN3 TRANS4, and FOCE-I. To explain inter-individual variability, we evaluated covariates from demographic, biochemical, and genetic data (single nucleotide polymorphisms [SNPs] related to the transport and metabolism of drugs). RESULTS: A two-compartment model was built using 483 data points from 45 patients (0.33-17.83 years of age) treated with MTX (0.25-5 g/m2) in different cycles. Serum creatinine (SCR), height (HT), blood urea nitrogen (BUN) and a low BMI stratification (according to the z-score defined by the World Health Organization [LowBMI]) were added as clearance covariates. The final model described MTX clearance as [Formula: see text]. In the two-compartment structural model, the central and peripheral compartment volumes were 26.8 L and 8.47 L, respectively, and the inter-compartmental clearance was 0.218 L/h. External validation of the model was performed through a visual predictive test and metrics using data from 15 other pediatric ALL patients. CONCLUSION: The first popPK model of MTX was developed for Brazilian pediatric ALL patients, which showed that inter-individual variability was explained by renal function and factors related to body size.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Metotrexato
/
Leucemia-Linfoma Linfoblástico de Células Precursoras
Tipo de estudo:
Prognostic_studies
Limite:
Child
/
Humans
País/Região como assunto:
America do sul
/
Brasil
Idioma:
En
Revista:
Pharm Res
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Brasil
País de publicação:
Estados Unidos